1. Field of the Invention
The present invention relates generally to the field of immunology and tumor biology. More particularly, it concerns compositions and methods involving bispecific antibodies for B-cell malignancy therapeutics and/or diagnostics.
2. Description of Related Art
The immune system of vertebrates consists of a number of organs and cell types which have evolved to accurately recognize foreign antigens, specifically bind to, and eliminate/destroy such foreign antigens. Lymphocytes, among other cell types, are critical to the immune system. Lymphocytes are divided into two major sub-populations, T cells and B cells. Although inter-dependent, T cells are largely responsible for cell-mediated immunity and B cells are largely responsible for antibody production (humoral immunity).
In humans, each B cell can produce an enormous number of antibody molecules. Such antibody production typically ceases (or substantially decreases) when a foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated and may result in a cancer known as a B cell lymphoma. B-cell lymphomas, such as the B-cell subtype of non-Hodgkin's lymphoma, are significant contributors to cancer mortality. The response of B-cell malignancies to various forms of treatment is mixed. For example, in cases in which adequate clinical staging of non-Hodgkin's lymphoma is possible, field radiation therapy can provide satisfactory treatment. Still, about one-half of the patients die from the disease (Devesa et al., 1987).
Acute leukemia is the most common childhood malignancy, representing 30% of all cancer in American children under the age of 15-19 years and 12% of cancer cases in those aged 15 to 19 years old. In the United States, approximately 2500 new cases are diagnosed annually; 80% of these are B lineage acute lymphoblastic leukemia (B-ALL). Chemotherapy resistant blasts are a frequent cause of treatment failure in all leukemia patients (List, 1996) and alternative therapies are urgently needed.
The majority of chronic lymphocytic leukemias are of the B-cell lineage (Freedman, 1990). This type of B-cell malignancy is the most common leukemia in the Western world (Goodman et al., 1996). The natural history of chronic lymphocytic leukemia falls into several phases. In the early phase, chronic lymphocytic leukemia is an indolent disease, characterized by the accumulation of small mature functionally-incompetent malignant B cells having a lengthened life span. Eventually, the doubling time of the malignant B cells decreases and patients become increasingly symptomatic. While treatment can provide symptomatic relief, the overall survival of the patients is only minimally affected. The late stages of chronic lymphocytic leukemia are characterized by significant anemia and/or thrombocytopenia. At this point, the median survival is less than two years (Foon et al., 1990). Due to the very low rate of cellular proliferation, chronic lymphocytic leukemia is resistant to cytotoxic drug treatment.
Traditional methods of treating B-cell malignancies, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. Therefore, there remains a need to develop novel treatments for B-cell malignancies with improved efficacy.